In the United States it is estimated that 2.7-3.9 million persons are living with chronic HCV infection, which accounts for approximately 1.3-1.9% of the population. Due to shared routes of transmission, co-infection with HCV occurs in 15-40% of persons chronically infected with human immunodeficiency virus (HIV). Now, in the context of effective combination antiretroviral therapy (ART), liver disease has emerged as a predominant cause of death and of healthcare resource utilization in HIV-infected persons. A recently discovered host single nucleotide polymorphism upstream of the IL28B gene (rs12989760) has been reported as a predictor of HCV treatment response, spontaneous viral clearance, lipoprotein levels, and steatosis. The interaction of HCV virions and lipoproteins is well described. The long-term objective of this research proposal is to determine the role of ART-induced lipoprotein increases on liver disease in HIV/HCV co-infected individuals. The objective will be achieved through several specific aims: (1) Explore the association of antiretroviral-induced lipoprotein increases on HCV pathogenesis in HIV/HCV co-infected patients;(2) Determine the effect of treatment with lipid lowering compounds on HCV pathogenesis in HIV/HCV co-infected patients;(3) In a candidate gene approach investigate the IL28B genotype as a host baseline predictor for risk of ART-related lipoprotein increases and increased HCV viral load in HIV/HCV co-infected patients at months 6 and 12 following ART initiation;(4) Determine the impact of the host genetics on differential ISG expression and lipoprotein biosynthesis in HIV/HCV co-infected patients at baseline and on pegIFN/RBV therapy. Specific Aim 1 will be achieved using a large well-described cohort repository to determine the correlation of increases in lipoprotein parameters and HCV RNA after the initiation of ART in HIV/HCV co-infected patients. Specific Aims 2 and 3 will be achieved using a prospective study design of HIV/HCV co-infected patients initiating ritonavir-boosted-protease inhibitor-based ART. Patients will be randomization into a lipid lowering therapy arm versus protease inhibitor therapy alone. Patient DNA will be collected at baseline for host genotyping. Specific Aim 4 will be achieved using a well-described clinical cohort of HIV/HCV co-infected patients treated with interferon based regimens for HCV;this will be done in collaboration with investigators at the NIAID. PBMCs will be used for gene expression microarray and baseline DNA will be used for host genotyping. These Specific Aims will help demonstrate the feasibility of more individualized therapy in HIV/HCV co-infected patients. The results will clarify the utility of further study in assessing the role of lipid lowering agents and the IL28B polymorphism in the treatment of HIV/HCV co-infected patients, especially in the era of new combination therapies that will include directly acting antivirals for the treatment of HCV. With improved SVR rates, but more expensive combination regimens, the ability to individualize treatment decisions regarding the utility and benefit of HCV therapy will be critical. PUBLIC HEALTH RELEVANCE (provided by the applicant): Due to shared routes of transmission, co-infection with HIV and HCV is common;in the context of effective combination antiretroviral therapy (ART), liver disease has emerged as a predominant cause of death and of healthcare resource utilization in HIV-infected persons. This study proposes to provide evidence for individualized therapy of HIV and HCV in the HIV/HCV co-infected patient population with a focus on antiretroviral induced metabolic complications and the IL28B gene polymorphism. Results from this study would directly translate to the clinical care of this difficult to treat patient population with the ultimate goal to improve long-term liver related morbidity and mortality.